BRCA1 (breast cancer susceptibility gene 1 (NM—007294.2)), is a tumor suppressor gene implicated in the hereditary predisposition to familial breast and ovarian cancers. A mutation in the BRCA1 gene significantly increases the risk of developing breast and ovarian cancer (Ford et al. Am J Hum Genet. 1998 62:676-689). Multiple references describe methods for treatment and/or diagnosis and/or prognosis of cancer based on BRCA1. See, e.g. U.S. Pat. No. 5,747,282.
BRCA1 is also involved in DNA repair and genome integrity (Scully and Livingston Nature 2000 408, 429-432). This nuclear protein has a role in DNA repair, transcription, ubiquitylation and cell cycle regulation (Deng et al. Bioessays 2000 22(8):728-737). BRCA1 potently inhibits genome instability by regulating expression of genes that are involved in DNA damage repair pathways (Deng et al. Hum Mol Genet. 2003 12 Spec No 1:R113-123). Murine embryos carrying a BRCA1-null mutation exhibit hypersensitivity to DNA damage and chromosomal abnormalities likely due to defective G2/M checkpoint control and improper centrosome duplication (Scully et al. Mol Cell. 1999 4(6):1093-1099; Somasundaram et al. Oncogene 1999 18(47):6605-6614). BRCA1-nullizygous mice show embryonic lethality in early stages of development that are associated with a proliferation deficit (Hakem et al. J Mammary Gland Biol Neoplasia 1998 3(4):431-445).
BRCA1 interacts directly and/or indirectly with many other proteins and signaling hubs including p53, which have been implicated in cardiac remodeling (Deng et al. Bioessays 2000 22(8):728-737). Although this relationship is complex, and contextual, recent studies demonstrate that BRCA1 exon11-knockout embryos die late in gestation as a result of widespread apoptosis but elimination of one p53 allele rescues this embryonic lethality (Xu et al. Nat Genet. 2001 28(3):266-271; Xu et al. Nat Genet. 1999 22(1):37-43).
BRCA1-deficient cells have been shown to have increased sensitivity to apoptosis induction in the presence of BARD1 and doxorubicin (Irminger-Finger et al. Molecular Cell 2001 8: 1255-1266; EP 1321522). Use of a BRCA1 construct in combination with BARD1 antisense to treat ischemic stroke or heart failure is suggested (EP 1321522).
WO 2006/015127 A2 describes using stem cells expressing at least one polypeptide selected from the group consisting of Oct4; DEK; BRCA1; Ect2; and MYC; at least one polypeptide selected from the group consisting of Fosb; NRAP; MEF2A; Furin; and TGFβ1; and at least one polypeptide selected from the group consisting of integral membrane protein 2A; insulin-like growth factor binding protein 4; thymus cell antigen 1, theta; selenoprotein P, plasma 1; and glycoprotein 38, for repairing cardiovascular tissue. The stem cells are administered to cardiovascular tissue and more specifically heart tissue.
Published U.S. Patent Application US 2006/0154252 discloses upregulation of BRCA1 during progression of an atherosclerotic plaque.
WO 2002/46466 describes use of a BRCA/STAT complex modulating compound comprising a STAT activating agent and a BRCA polypeptide or functional fragment thereof to inhibit cellular proliferation mediated by a BRCA/STAT complex. BRCA/STAT complex modulating compounds are suggested to reduce the rate or extent of proliferation useful in treating an individual having a vascular proliferative disorder such as atherosclerosis (WO 2002/46466).